Alcohol abuse is a prevalent public health problem entailing significant socioeconomic costs. Alcoholics experience physical withdrawal symptoms, depressed mood and negative affect, all of which contribute to alcohol-related stress. These stress-related symptoms are especially thought to set the stage for relapse in many alcoholics, contributing to the challenge of the treatment of alcoholism. Despite the prevalence and detrimental consequences of alcohol abuse, comparatively little is known about its neurobiological basis or treatment. Recent evidence suggests that kappa opioids may be a key mediator in the stress-related effects of drugs of abuse. The proposed experiments will aim to examine kappa opioid regulation of stress-related behaviors following chronic ethanol exposure, and the involvement of kappa opioid mechanisms in the reinstatement of ethanol seeking. Specific Aim 1 of this proposal will evaluate the role of the kappa opioid system in the regulation of stress-related behavior, using the elevated plus maze model of anxiety in rats, via kappa opioid receptor activation and exposure to external stressors. Taken together with the results of the Preliminary Study, experiments proposed under this Specific Aim would provide further insights to the interactions between kappa opioid mechanisms, alcohol withdrawal and stress. Using a conceptually similar strategy, Specific Aim 2 will compare the extent to which activation of the kappa opioid system and exposure to a mild external stressor enhance the behavioral response to stress following a protracted period of abstinence from ethanol. These experiments aim to provide further information regarding the long-lasting neurobiological changes associated with withdrawal. With regard to relapse, Specific Aim 3 will determine the extent to which persistent ethanol-seeking behavior following abstinence, including stress-induced relapse, is regulated by kappa opioid mechanisms using the reinstatement model. Results obtained from the proposed studies under this Specific Aim would aid in the identification of novel mechanisms for the prevention of alcohol relapse. Overall, this proposal will further our understanding of the role of kappa opioid mechanisms in the regulation of alcohol-related stress and subsequent relapse. Determining the underlying neuropharmacological mechanisms of these physiological and behavioral adaptations would aid in the development of pharmacotherapies for the long-term management of alcoholism. PUBLIC HEALTH RELEVANCE: Alcohol abuse is a significant public health problem that leads to more than 25,000 deaths and over $100 billion in total annual costs in the United States alone. Stress-related symptoms, such as feelings of anxiety, have been reported to lead to relapse in many alcoholics, contributing to the challenge of the treatment of alcoholism. This proposal aims to investigate the role of the kappa opioid neurochemical system, which is thought to be a key mediator in the stress-related effects of drugs of abuse, in the physiological and behavioral adaptations associated with continued alcohol abuse in order to aid in the development of pharmacotherapies for the long-term management of alcoholism.